Cholesterol causes hardening of the arteries, but for unknown reasons this mostly occurs in patients with inflammation. Cholesterol is a major component of lipid rafts, which are areas on cell surfaces that concentrate signaling molecules. These signals include calcium entry into cells, which activates white blood cells and causes inflammation.
Many inflammatory cell responses are tightly controlled by the regulated entry of Ca2+ ions into the cell. Because innate immune cells lack voltage-gated calcium channels, processes like chemotaxis, phagocytosis, respiratory burst and degranulation in response to G-protein coupled (GPC) mediators depend in great measure on store-operated calcium entry (SOCE) into the cell. SOCE is the second phase of a biphasic, agonist-activated Ca2+ mobilization mechanism that is found in essentially all “non-excitable” eukaryotic cells. This process is initiated when GPC receptors linked to Gi or Gq, or when receptor tyrosine kinases that couple to phospholipases activate Phospholipase C (PLC). PLC breaks down PIP2 to inositol (1,4,5) triphosphate (InsP3) and diacylglycerol. InsP3 diffuses to the endoplasmic reticulum where it depletes InsP3-sensitive calcium stores and thus activates SOCE.
Diacylglycerol also has the intrinsic capacity to activate calcium entry channels. Thus in fact, total “stimulated calcium entry” in native cells is probably the additive result of several processes including store depletion that can initiate Ca2+ channel gating. This is clearly the case in the neutrophil (PMN). The complex group of mechanisms by which calcium entry is stimulated is still poorly understood. Nonetheless, as disclosed in Itagaki et al., “Sphingosine 1-phosphate, a diffusible calcium influx factor mediating store-operated calcium entry,” J. Biol. Chem., 278(30), 27540-7 (2003), sphingosine 1-phosphate (S1P) acts in the PMN as a second messenger, and links GPC store depletion to Ca2+ entry. It was further shown in Itagaki et al., “Lysophosphatidic acid triggers calcium entry through a non-store-operated pathway in human neutrophils,” J. Leukoc. Biol., 181-9 (2005) [e-pub., Nov. 2, 2004] that related lysophospholipids, like lysophos-phophatidic acid (LPA), act similarly in PMN and other systems. The mechanisms by which S1P and related lysophospholipids gate calcium entry into cells, however, remain entirely unknown, so that a means by which calcium entry can be regulated to modulate inflammatory cell response is also not understood.